12-102839200-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000277.3(PAH):​c.1334G>T​(p.Cys445Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

PAH
NM_000277.3 missense

Scores

8
2
9

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.92
Variant links:
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000277.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAHNM_000277.3 linkuse as main transcriptc.1334G>T p.Cys445Phe missense_variant 13/13 ENST00000553106.6
PAHNM_001354304.2 linkuse as main transcriptc.1334G>T p.Cys445Phe missense_variant 14/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.1334G>T p.Cys445Phe missense_variant 13/131 NM_000277.3 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Phenylketonuria Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Aug 17, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Benign
22
DANN
Benign
0.92
DEOGEN2
Pathogenic
0.83
D;D
Eigen
Benign
0.035
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.9
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.3
N;N
REVEL
Pathogenic
0.68
Sift
Benign
0.066
T;T
Sift4G
Benign
0.064
T;T
Polyphen
0.071
B;.
Vest4
0.72
MutPred
0.72
Gain of disorder (P = 0.1554);.;
MVP
0.92
MPC
0.056
ClinPred
0.93
D
GERP RS
4.4
Varity_R
0.64
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1874484048; hg19: chr12-103232978; COSMIC: COSV61014353; COSMIC: COSV61014353; API